Platelet-activating factor (PAF) has recently been identified as an acetyl glyceryl ether phosphorylcholine (AGEPC), i.e., 1-O-hexadecyl/octadecyl-2-O-acetyl-sn-glycero-3-phosphorylcholine (Hanahan, D. S. et al., J. Biol. Chem., 255: 5514, 1980). It is a potent lipid mediator of inflammation and anaphylaxis and is produced by stimulated basophils, neutrophils, platelets, macrophages, endothelial cells, and IgE-sensitized bone marrow mast cells. PAF exerts a myriad of biological actions. It induces smooth-muscle contraction, aggregration, chemotaxis, and degranulation of neutrophil and heightened metabolic activity of macrophages in vitro. It also reduces coronary blood flow and contractile force of isolated guinea pig heart, leading to cardiac anaphylaxis. In various animal models, PAF induces bronchoconstriction, hyperalgesia, hypotension, neutropenia, thrombocytopenia, increased cutaneous vascular permeability, increased hematocrit, and lysosomal enzyme secretion. In man, intradermal injection of PAF at 0.1 .mu.g per site elicits a biphasic inflammatory response, which is potentiated by prostaglandin E.sub.2. Thus, PAF has been linked to various biologic activities and pathways making it one of the important mediators responsible for a variety of physiological process which are known to be associated with a large group of diseases, for example, inflammatory diseases, cardiovascular disorders, asthma, lung edema, endotoxin shock syndrome, and adult respiratory distress syndrome.
The compounds of the present invention are potent and specific PAF-antagonists. They belong to the class of neolignan compounds related to piperenone, a known insect antifeeding substance, and 5-allyl-2-(3,4-dimethoxyphenyl)-3a,.alpha.-methoxy-3-methyl-2,3,3a,6-tetra hydro-6-oxobenzofuran, the subject matter of copending application Ser. No. 541,806, filed Oct. 13, 1983 now U.S. Pat. No. 4,540,709. Both piperenone and the 5-allyl compound mentioned above were isolated from the Chinese herbal plant Piper futokadzsura Sieb. See K. Matsui et al., Agr. Biol. Chem. 40, 1045 (1976); ibid, 40, 1113 (1976); and Matsui et al., Tetrahedron Letters 24, 1905 (1975). Although the plant has been used in Chinese herbal medicine for the treatment of arthritic conditions, no one had successfully isolated nor identified the active substance until our work on the 5-allyl compound and the compounds of the present invention. We found these compounds to be potent and specific PAF-antagonists useful not only in the treatment of arthritic conditions but also for other diseases including asthma, hypertension, lung-edema, endotoxin shock syndrome, adult distress syndrome and the like.
Accordingly, it is the object of the present invention to provide a class of novel compounds as specific PAF-antagonists.
Another object of this invention is to provide processes for the preparation of these PAF-antagonists.
A further object of this invention is to provide a pharmaceutically acceptable composition containing these novel compounds as the active ingredient for the treatment of diseases which are subject to the mediation of PAF.
Still a further object of this invention is to provide a method of treatment comprising the administration of a therapeutically sufficient amount of one or more of the PAF-antagonists to a patient suffering from various skeletal-muscular disorders including but not limited to inflammation, e.g., osteoarthritis, rheumatoid arthritis and gout; allergic disorders; hypertension; cardiovascular disorder; asthma; lung edema; skin diseases; psoriasis; endotoxin shock syndrome; or adult respiratory distress syndrome.